Iodinane- and metal-free synthesis of N-cyano sulfilimines: Novel and easy access of NH-sulfoximines

Article abstract of DOI:10.1021/ol7016577

The synthesis of W-cyanosulfilimines can readily be achieved by reaction of the corresponding sulfides with cyanogen amine in the presence of a base and NBS or l₂ as halogenating agents. Oxidation followed by C-N bond cleavage affords synthetically useful WH-free sulfoximines.

Full text of DOI:10.1021/ol7016577

ORGANIC
LETTERS
2007
Vol. 9, No. 19
3809-3811
Iodinane- and Metal-Free Synthesis of
N-Cyano Sulfilimines: Novel and Easy
Access of NH-Sulfoximines
Olga Garc´ıa Manchen˜o, Olivia Bistri, and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen UniVersity, Landoltweg 1,
D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received July 13, 2007
ABSTRACT
The synthesis of N-cyanosulfilimines can readily be achieved by reaction of the corresponding sulfides with cyanogen amine in the presence
of a base and NBS or I2 as halogenating agents. Oxidation followed by C−N bond cleavage affords synthetically useful NH-free sulfoximines.
The development of novel methods for the preparation of
sulfilimines and sulfoximines has attracted significant atten-
tion over the past few years, since some derivatives proved
useful as building blocks of chiral ligands1 and structural
units in pseudopeptides.2 Two main routes are commonly
followed to prepare these compounds.3 They either involve
an oxidative imination of a sulfide or sulfoxide or they utilize
a nucleophilic displacement of the corresponding sulfin- or
sulfonimidoyl halide or sulfonimidate.
attention on sulfur iminations using cyanogen amine as
nitrogen source.5 In that context, we demonstrated that
N-cyanosulfoximines were very appealing substrates for the
preparation of N-heterocyclic sulfoximines.
Being attracted by the possibility of performing metal-
free N-cyanosulfilimines syntheses,6 we aimed to further
simplify the synthetic protocol by avoiding the use of
hypervalent iodinanes such as PhI(OAc)2. For achieving this
goal, an in situ formation of a sulfinimidoyl halide followed
by a nucleophilic substitution with cyanogen amine was
envisaged.7 Herein, we report an easy procedure for the
synthesis of various N-cyanosulfilimines, based on the use
of low-cost reagents such as NBS or I2. Furthermore, we
demonstrate that N-cyanosulfilimines are valuable intermedi-
ates for the preparation of N-cyano- and NH-sulfoximines.
For the initial screening, benzyl methyl sulfide (1a) was
chosen as substrate. First, the reaction of 1a with cyanogen
In our own search for new and more efficient syntheses
of sulfilimines and sulfoximines,4 we recently focused our
(1) For examples of sulfoximines as chiral ligands, see: (a) Bolm, C.;
Simic, O. J. Am. Chem. Soc. 2001, 123, 3830. (b) Harmata, M.; Ghosh, S.
K. Org. Lett. 2001, 3, 3321. (c) Bolm, C.; Martin, M.; Simic, O.; Verrucci,
M. Org. Lett. 2003, 5, 427. (d) Bolm, C.; Verrucci, M.; Simic, O.; Cozzi,
P. G.; Raabe, G.; Okamura, H. Chem. Commun. 2003, 2816. (e) Bolm, C.;
Martin, M.; Gescheidt, G.; Palivan, C.; Neshchadin, D.; Bertagnolli, H.;
Feth, M. P.; Schweiger, A.; Mitrikas, G.; Harmer, J. J. Am. Chem. Soc.
2003, 125, 6222. (f) Langner, M.; Bolm, C. Angew. Chem., Int. Ed. 2004,
43, 5984. (g) Mo¨ssner, C.; Bolm, C. Angew. Chem., Int. Ed. 2005, 44, 7564.
(h) Langner, M.; Re´my, P.; Bolm, C. Synlett 2005, 781. (i) Langner, M.;
Re´my, P.; Bolm, C. Chem. Eur. J. 2005, 11, 6254. (j) Reetz, M. T.;
Bondarev, O. G.; Gais, H.-J.; Bolm, C. Tetrahedron Lett. 2005, 46, 5643.
(2) For the use of sulfoximines as building blocks for pseudopeptides,
see: (a) Bolm, C.; Kahmann, J. D.; Moll, G. Tetrahedron Lett. 1997, 38,
1169. (b) Bolm, C.; Moll, G.; Kahmann, J. D. Chem. Eur. J. 2001, 7, 1118.
(c) Tye, H.; Skinner, C. L. HelV. Chim. Acta 2002, 85, 3272. (d) Bolm, C.;
Mu¨ller, D.; Hackenberger, C. P. R. Org. Lett. 2002, 4, 893. (e) Bolm, C.;
Mu¨ller, D.; Dalhoff, C.; Hackenberger, C. P. R.; Weinhold, E. Bioorg. Med.
Chem. Lett. 2003, 13, 3207.
(4) For previous contributions on iminations of sulfur compounds, see
the following references. Rh-catalyzed: (a) Okamura, H.; Bolm, C. Org.
Lett. 2004, 6, 1305. Ag-catalyzed: (b) Cho, G. Y.; Bolm, C. Org. Lett.
2005, 7, 4983. Metal-free: (c) Cho, G. Y.; Bolm, C. Tetrahedron Lett.
2005, 46, 8007. Fe-catalyzed: (d) Garc´ıa Manchen˜o, O.; Bolm, C. Org.
Lett. 2006, 8, 2349. For comparative metal-catalyzed iminations of
sulfoxides, see: (e) Garc´ıa Manchen˜o, O.; Bolm, C. Chem. Eur. J. 2007,
13, 6674.
(5) Garc´ıa Manchen˜o, O.; Bolm, C. Org. Lett. 2007, 9, 2951.
(6) For previous synthesis of N-cyanosulfilimines, see: (a) Swern, D.;
Ikeda, I.; Whitfield, G. F. Tetrahedron Lett. 1972, 13, 2635. (b) Hutchins,
M. G. K.; Swern, D. Tetrahedron Lett. 1981, 22, 4599. (c) Kemp, J. E. G.;
Ellis, D.; Closier, M. D. Tetrahedron Lett. 1979, 20, 3781. (d) Zhu, Y.;
Rogers, R. B.; Huang, J. X. US 20050228027 A1.
(3) For recent reviews, see: (a) Reggelin, M.; Zur, C. Synthesis 2000,
1. (b) Harmata, M. Chemtracts 2003, 16, 660. (c) Okamura, H.; Bolm, C.
Chem. Lett. 2004, 33, 482. (d) Bentley, R. Chem. Soc. ReV. 2005, 34, 609.
10.1021/ol7016577 CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/16/2007

amine and NBS in the presence of t-BuOK was carried out
in methanol (Table 1, entry 1). Under these conditions
Table 2. Optimization: Effect of the Halogen Sourcea
Table 1. Imination of Sulfide 1aa
entry halogen source
t-BuOM
yield of 2ab (%) 2a/3ac
1
2
3
4
5
6
7
NCS
NBS
Br2
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
nd
83
nd
33
39
55
81
45:55
90:10
2:98
100:0
100:0
100:0
100:0
entry
solvent
MeOH
dry MeOH
MeOH/H2O (4:1)
dry MeOH + MS 4Å
EtOH
t-BuOH
MeCN
THF
THF
base
2a/3ab
NIS
I2
1
2
3
4
5
6
7
8
9
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
NaH
85:15 to 90:10
71:29
87:13
16:84
64:36
2:98
88:12
71:29
90:10
d
I2
I2
d
a Reaction conditions: Sulfide 1a (1 equiv), base (1.2 equiv), H2NCN
(1.3 equiv), and halogen source (1.5 equiv) in MeOH at room temperature.
b Yield after column chromatography. c The 2a/3a ratio was determined by
1H NMR of the crude mixture. d Use of 4 equiv of I2.
10
MeOH
K2CO3
in 39% yield, use of 4 equiv of the dihalide afforded 2a in
55% yield (entry 6). Finally, t-BuONa proved to be a more
efficient base, improving the yield of 2a to 81% (entry 7).
Next, the substrate scope of this imination reaction was
investigated (Table 3). A variety of sulfides were treated with
a Reaction conditions: sulfide 1a (1 equiv), base (1.2 equiv), H2NCN
(1.3 equiv), and halogen source (1.5 equiv) at room temperature. b The 2a/
3a ratio was determined by H NMR of the crude mixture.
1
N-cyanosulfilimine 2a was the major product. However, the
formation of 10-15% of the corresponding sulfoxide 3a was
also observed. In order to avoid this side product, the effect
of the solvent was explored (Table 1).
Table 3. Substrate Scopea
Neither the use of dry or degassed MeOH (entry 2) nor
the addition of water (entry 3) helped to increase the ratio
of 2a/3a.8 Moreover, the addition of molecular sieves 4 Å
dramatically favored the formation of the sulfoxide (entry
4). THF and other alcohols such as EtOH and t-BuOH were
also tested. Finally, with t-BuOK as base, MeOH and MeCN
provided the highest 2a/3a ratios (entries 1 and 7).9
The role of the base was also evaluated. Sulfoxide
formation was observed in a similar 2a/3a ratio (90:10) when
NaH was used (entry 9). Finally, no reaction occurred when
the weaker base K2CO3 was employed (entry 10).
Next, the effect of the halogen source on the 2a/3a ratio
was evaluated with methanol as solvent (Table 2).
To our delight, we found that the use of iodine instead of
NBS as halogenating agent (in combination with t-BuOK)
led to the exclusive formation of sulfilimine 2a. Whereas
with 1.2 equiv of I2 the desired product was only obtained
halogen yield of
source
entry
R, R′
Ph, Me
sulfide
2b (%)
2/3c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1b
NBS
I2
91
67
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
nd
p-OMeC6H4, Me
p-NO2C6H4, Me
2-Naph, Me
2-Py, Me
1c
1d
1e
1f
NBS
I2
95
90
NBS
I2
92
30
NBS
I2
85
70
NBS
I2
95
58
Ph, Ph
1g
1h
1i
NBS
I2
NBS
I2
NBS
I2
99
<10
83
<10
71
<10
-(CH2)2-
90:10
nd
100:0
nd
(7) For previous examples of nucleophilic substitution with amides or
aromatic amines, see: (a) Ringer, J. W.; Pearson, D. L.; Scott, C. A.; Wallin,
A. P.; WO 9821178. (b) Vilsmaier, E.; Reichert, K. Liebigs Ann. Chem.
1980, 1075. (c) Tseng, C. P. US 4484939. (d) Mock, W. L.; Tsay, J. T.
Synth. Commun. 1988, 8, 769. (e) Shimizu, H.; Ikedo, K.; Hamada, K.;
Ozawa, M.; Matsumoto, H.; Kamata, K.; Nahamura, H.; Ji, M.; Kataoka,
T.; Hori, M. J. Chem. Soc., Perkin Trans. 1 1991, 7, 1733. (f) Nummy, L.
J.; EP 598396. (g) Benin, V.; Kaszynski, P.; Pink, M.; Young, V. G. J.
Org. Chem. 2000, 65, 6388. (h) Zienkiewicz, J.; Kaszynski, P.; Young, V.
G. J. Org. Chem. 2004, 7, 2551. (i) Hamilton, C. T. US 2005215570 A1.
(j) Kislitsyn, P. G.; Kuchero, F. A.; Chukhrov, L. N.; Zlotin, S. G.; Satrikova,
Z. A.; Dolgushin, F. M., Russ. Chem. Bull. 2004, 4, 916.
(8) For NBS-mediated oxidations of sulfides in aqueous media, see:
Surenda, K.; Krishnaveni, N.; Srilakshmi, K.; Pavan, V.; Sridhar, R.; Rao,
K. Tetrahedron Lett. 2005, 46, 4581.
(9) The 2a/3a ratio did not improve when the reaction was carried out
at 0 °C (80:20).
t-Bu, Me
a Reaction conditions: sulfide 1 (1 mmol, 1 equiv), H2NCN (1.3 equiv),
and the combination of NBS (1.5 equiv)/t-BuOK (1.2 equiv) or I2 (4.0
equiv)/t-BuONa (1.2 equiv) in MeOH (3 mL) at room temperature. b Yield
after column chromatography. c The 2a/3a ratio was determined by 1H NMR
of the crude mixture.
NBS or I2 in MeOH to form cyanosulfilimines 2. Both
halogenating agents showed a high selectivity in the forma-
tion of the sulfilimines, with iodine providing lower yields
compared to NBS (entries 2, 4, 6, 8, and 10). Moreover,
3810
Org. Lett., Vol. 9, No. 19, 2007

attempted conversions of diarylsulfide 1g and dialkylsufides
1h and 1i remained unsuccessful in reactions with iodine
(entries 12, 14, and 16), whereas transformations with NBS
led to the corresponding sulfilimines in satisfying yields (up
to 99%; entries 11, 13, and 15). Only the NBS-mediated
reaction of sulfide 1h, which possessed two R-methylenic
substituents, showed a lower selectivity, affording a 90:10
mixture of sulfilimine 2h and sulfoxide 3h (entry 13).10 This
result was consistent with the one observed in the conversion
of sulfide 1a, which also had methylene protons.
Finally, we were pleased to find that in the case of
reactions with sulfides 1b-g and 1i, which have no R-meth-
ylenic positions, the formation of the corresponding sulfox-
ides was not detected, even when NBS was used as
halogenating agent (Table 3, entries 1-12 and 15).
In order to demonstrate the synthetic value of the prepared
N-cyanosulfilimines 2, they were converted into trifluoro-
acetyl-protected and free NH-sulfoximines 5 and 6, respec-
tively. Interestingly, the latter transformation only required
three steps, with no need of purification between the two
final ones (Scheme 1).
Table 4. Synthesis of NH-Sulfoximines from Sulfilimines 1a
yield of yield of yield of
entry
R, R′
Bn, Me
sulfilimine 4b (%)
5b (%)
6
b,c (%)
1
2
3
4
5
6
7
9
2a
2b
2c
2d
2e
2f
62
86
78
63
76
82
99
86
84
93
99
47
93
92
93
95
81
72
99
42
98
54
92
66
Ph, Me
p-OMeC6H4, Me
p-NO2C6H4, Me
2-Naph, Me
2-Py, Me
Ph, Ph
-(CH2)2-
2g
2h
a See the Supporting Information for reaction conditions. b Yield after
column chromatography. c Yield over two steps from 4.
TFAA, and trifluoroacetyl-protected sulfilimine 7 was ob-
tained in 99% yield (Scheme 2).
Scheme 2
Scheme 1
In summary, we reported the synthesis of N-cyanosulfil-
imines from readily available sulfides and cyanogen amine
using NBS or I2 as halogenating reagents. The preparation
of their corresponding N-cyanosulfoximines was easily
achieved by common oxidation with m-CPBA under basic
conditions. Finally, the access to synthetically valuable NH-
sulfoximines was accomplished in two steps involving
treatment with TFAA and subsequent methanolysis of the
intermediately formed N-trifluoroacetyl sulfoximines.
Overall the described four-step-procedure for the formation
of free NH-sulfoximines starting from sulfides has several
advantages over the existing methodologies: the reagents
involved are non-explosive, easy to handle, mild, and stable
toward atmospheric moisture and oxygen. Thus, neither dried
solvents nor an inert atmosphere are required.
First, oxidation of 2 with m-CPBA afforded the N-
cyanosulfoximines 4 in good yields (62-86%). The N-cyano
group proved to be easily cleaved upon treatment with TFAA
affording N-trifluoroacetylsulfoximines 5 (47-99%). Finally,
sulfoximines 5 were converted into NH-free sulfoximines 6
by methanolysis of the trifluoroacetyl moiety (42-99%).4a
For all substrates, each step of this sequence proceeded with
high yields, except in the cases of the 2-pyridyl- and
p-nitrophenyl-substituted compounds 2d and 2f (Table 4,
entries 4 and 6, respectively). There, the final deprotection
of these sulfoximines possessing electron-withdrawing groups
occurred with only moderate yields (42% and 54%).
Acknowledgment. The Fonds der Chemischen Industrie
is gratefully acknowledged for financial support. O.G.M. and
O.B. thank the Spanish Ministerio de Educacio´n y Ciencia
(M.E.C.) and the Alexander von Humboldt Foundation,
respectively, for postdoctoral fellowships.
Supporting Information Available: Experimental pro-
cedures, full characterization of new compounds, and 1H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
With the goal to expand the applicability of the cyano
group cleavage, N-cyanosulfilimine 2b was subjected to
(10) When the reaction of 1h was carried out on 10 mmol scale, a 60:40
ratio 2h/3h was observed and sulfilimine 2h was isolated in 50% yield.
OL7016577
Org. Lett., Vol. 9, No. 19, 2007
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